Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO

We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics. Analysis of meningioma gene expression data for each mutation subtype. Includes gene expression data from 75 unique meningiomas and 39 replicates.

本研究对300例脑膜瘤 (meningiomas)——最常见的原发性脑肿瘤——开展了基因组分析，在近四分之一的脑膜瘤中发现了TRAF7的突变，TRAF7是一种促凋亡型E3泛素连接酶 (proapoptotic E3 ubiquitin ligase)。TRAF7突变常与KLF4的复发性突变K409Q同时发生，KLF4是一种以诱导多能性功能闻名的转录因子；或与AKT1(E17K)突变共存，该突变可激活PI3K信号通路 (PI3K pathway)。在约5%的非NF2突变型脑膜瘤中，检测到了可激活Hedgehog信号通路 (Hedgehog signaling)的SMO突变。此类非NF2突变型脑膜瘤具有独特的临床特征：几乎均为良性，染色体稳定性 (chromosomal stability)良好，起源于颅底内侧区。与之相反，携带NF2突变和/或22号染色体缺失的脑膜瘤更易表现为非典型性，存在基因组不稳定性 (genomic instability)，且多位于大脑及小脑半球。综上，本研究明确了不同的脑膜瘤亚型，为靶向治疗 (targeted therapeutics)提供了研究方向。本研究对各突变亚型脑膜瘤的基因表达数据进行了分析，数据集包含75例独立脑膜瘤样本及39份重复样本。